The most common tumor to metastasize to the skin is breast cancer. These skin deposits show remarkably different growth patterns with distinct angiogenic profiles. In a study of 51 surgically resected cutaneous deposits , 26 cases had an infiltrative growth pattern: The carcinoma cells infiltrated between preexisting dermal structures without significant disturbance of the dermal architecture. In nine cases, the growth pattern was expansive, the dermal deposit forming a well-circumscribed nodule consisting of carcinoma cells and reactive vascular tumor stroma. Preexisting dermal structures were pushed aside by the expansively growing nodule. The growth pattern was mixed infiltra-tive-expansive in the remaining 16 cases, meaning that these deposits consisted of a central expansive nodule surrounded by carcinoma cells showing an infiltrative growth pattern. The interobserver consistency of the assignment of the cutaneous deposits to the different growth pattern categories was 92 percent. The growth pattern of the skin deposit was positively correlated with the growth pattern of the respective primary tumor.
Cutaneous deposits with an infiltrative growth pattern only rarely contained necrosis or a fibrotic focus and infrequently showed expression of CA IX in a minority of tumor cells, whereas these histological markers of intratumoral hypoxia were significantly more frequent in deposits containing an expansive nodule (expansive and mixed growth patterns). These differences in hypoxia markers between the growth patterns were reflected in differences in angiogene-sis. Microvessel density, quantified by the Chalkley method, was significantly higher in the expansive and mixed growth patterns than in the infiltrative growth pattern. Mean Chalk-ley count was higher when a fibrotic focus was present and when CA IX was expressed. The fraction of proliferating endothelial cells was highest in the expansive growth pattern, intermediate in the mixed pattern, and low in the infiltrative growth pattern.
One major mechanism by which oxygen deficiency stimulates angiogenesis is hypoxia-modulated gene expression, including activation of vascular endothelial growth factor (VEGF) gene transcription. VEGF is also known as the vascular permeability factor and induces the extravasation of plasma proteins, including fibrinogen and prothrombin. VEGF also induces the expression of tissue factor on the endothelial cells, as does hypoxia. Tissue factor, which is also present in the subendothelial matrix and on many tumor cells, triggers the formation of fibrin by activation of thrombin and subsequent polymerization of thrombin-cleaved fibrinogen. Fibrin is an essential component of the provisional matrix that supports tissue remodeling, angiogenesis, and tumor growth. In the cutaneous breast cancer deposits, fibrin was present in all deposits with an expansive growth pattern, but in fewer than half of the deposits with an infiltrative pattern. The deposition of fibrin was positively correlated with microvessel density and with endothelial cell proliferation fractions.
The distinct angiogenic profiles in the different growth pattern categories of cutaneous breast cancer deposits may have important consequences for therapy. Different degrees of angiogenesis may predict a different response to anti-angiogenic therapy.
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